Calcitonin is a peptide hormone composed of 32 amino acids and produced by C-cells of the thyroid gland in mammals. Eight forms of calcitonin in five species, including man, pig, and salmon, are known. Calcitonins have been approved by regulatory agencies for the treatment of osteoporosis. In addition, published medical and research studies have suggested roles for calcitonin in other physiological and pathophysiological processes including: osteopenia and osteoporosis in men and women, risk of vertebral and nonvertebral fractures, Paget's disease, bone fracture or deficiency, primary or secondary hyperparathyroidism, periodontal disease or defect, metastatic bone disorder, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, post-dental implantation, periodontal disease, hypercalcemia, bone pain, general pain and hyperalgesia, conditions associated with inhibiting gastric secretion, other gastrointestinal disorders, osteoarthritis and rheumatoid arthritis (pain, bone loss, and joint destruction), renal osteodystrophy, obesity by induction of satiety, and male infertility.
As one example, osteoporosis (OP) is a disease of the skeleton in which the amount of calcium present in the bones slowly decreases to the point where bones become brittle and prone to fracture. One type of OP occurs in women due to postmenopausal decreases in estrogen levels. The decline of estrogen, in turn, results in a rapid depletion of calcium from the skeleton. Often women with postmenopausal OP experience vertebral fractures (collapse of the spine), as well as fractures of the hip, wrist, and forearm resulting from minor impact or falls.
Another type of OP, often termed “low turnover” OP, results when the on-going processes of bone resorption and formation no longer coordinate. Bone resorption, and hence calcium release from the bone, is a result of cells known as osteoclasts, that breakdown the skeleton. Osteoblasts, on the other hand, rebuild the skeleton through collagen, calcium, and phosphorous deposition. Often, over time, bone resorption overcomes bone formation thereby resulting in the loss of bone density. This type of OP affects both men and women.
In the regulation of bone calcification, an elevation of serum calcium triggers the release of calcitonin. Calcitonin inhibits the formation and activity of osteoclast cells by acting upon specific calcitonin receptors and, in turn, lowers serum calcium levels. Calcitonin's action is opposite to that of parathyroid hormone (PTH) in that calcitonin prevents loss of calcium from bone, results in an increase in the deposition of calcium and phosphate in bone and lowers the level of calcium in the blood.
As noted above, calcitonins of various species have been used for the treatment of osteoporosis, most notably salmon calcitonin. A calcitonin mimetic, however, would circumvent issues particular to the calcitonin peptide, such as antibody production, short half-life and bioavailability variations. Thus, there is a need for calcitonin agonists for use in the treatment and prevention of diseases and conditions characterized by abnormal calcification as well as in conditions wherein calcitonin would have a beneficial pharmacological effect. Such conditions and diseases include, without limitation: osteopenia and osteoporosis in men and women; reduction in the risk of fractures, both vertebral and nonvertebral; Paget's disease; bone fracture or deficiency; primary or secondary hyperparathyroidism; periodontal disease or defect; metastatic bone disorder; osteolytic bone disease; post-plastic surgery; post-prosthetic joint surgery; post-dental implantation; hypercalcernia; bone pain, general pain, and hyperalgesia; conditions associated with inhibiting gastric secretion; gastrointestinal disorders; osteoarthritis and rheumatoid arthritis (pain, bone loss, and joint destruction); renal osteodystrophy; obesity by induction of satiety; and male infertility.